Unit - III W

Department of Chemistry Sri Sarada Niketan College of Arts & Science for Women Kanavaipudur.

UNIT - III

Vitamins

The vitamins are a group of complex organic compounds required in small quantities by the

body for the maintenance of good health.

They are not normally synthesized in the body and hence they should be supplied by the diet.

The vitamins are present in foods in small quantities.

Classification

Vitamins are generally classified into two main groups. They are,

1. Fat soluble vitamins – Vitamin A, D, E and K

2. Water soluble vitamins – Vitamin B complex (B1, B2, B6 and B12) and C

Vitamin A

Occurrence

Vitamin A is present in almost all species of fish, birds and mammals.

The liver of any animal is a rich source of vitamin A.

Milk, egg yolk, dark green leafy vegetables and deep yellow vegetables and fruits are rich in

carotenes, which can be converted into vitamin A by the intestinal wall.

Biological importance

Vitamin A is essential

for the growth and metabolism of all body cells

for the formation of rhodopsin (visual purple) a complex substance formed from retinol and

protein. Rhodopsin, a pigment found in retina is necessary for vision in dim light.

for the maintenance of healthy skin, particularly mucous membrane of the cornea and the lining

of respiratory tract.

Requirements


Vitamin A requirement is based on the intake to maintain the normal blood level.

Recommended amount of vitamin A for different age group is as follows,

Infants - 1500 IU / day

Children - 2000 – 3000 IU / day

Adults - 5000 IU / day

Pregnant &

Lactating women - 6000 – 8000 IU / day (IU = International units)

Deficiency

The earliest sign of vitamin A deficiency is concerned with vision. Initially there is a loss of

sensitivity to green light, followed by impairment (CWtpistpj;jy;, jPq;Fnra;jy;) to adapt to

dim light. This condition leads to night blindness.

More prolonged or severe deficiency leads to the ulceration of cornea and this condition is

known as xerophthalmia or keratomalacia.

Structure

Thiamine (Vitamin B1)

Occurrence

It is present in cereals (gUg;G tiffs;). This vitamin is concentrated in the outer germ and

grain layers.

During milling and polishing this vitamin is discarded. Hence unpolished rice is the richest

source.

Rice polishing and yeast have been the usual sources of thiamine. Eggs are also a rich source.



Thiamine is a co-enzyme in many enzyme systems. These are involved principally in the

breakdown of glucose to yield energy.

Thiamine also helps in the formation of ribose, a sugar that is an essential constituent of DNA

and RNA.

The adequate level of thiamine provides healthy nerves, a good mental outlook, a normal

appetite and food digestion.

Requirements

The requirement of thiamine depends on energy expenditure.

Infants - 0.3 – 0.5 mg / day

Children - 0.7 – 1.2 mg / day

Adults - 1.2 – 1.5 mg / day

Pregnant &

Lactating women - 1.3 – 1.5 mg / day

Deficiency

Early symptoms of thiamine deficiency include fatigue (fisg;G, Nrhu;T), irritability (vspjpy;

Nfhgk; nfhs;fpw), depression (kd mOj;jk;) and numbness (czw;tw;w) of the leg and

constipation.

Beriberi sometimes called rice-eaters disease. Beriberi is characterized by edema (ePu; tPf;fk;) in

the legs. Thus, this vitamin is the antineuritic factor and hence the name aneurin.

Structure

Structural elucidation of Thiamine


1. The molecular formula of thiamine is C12H18ON4Cl2S.

2. When thiamine is treated with a sodium sulphite solution at room temperature, it is decomposed into

two compounds which are shown below.

If we derive the structures for compounds A and B, then we can elucidate the structure of

thiamine.

Structure of compound A

1. Molecular formula of compound A is C6H9ONS.

2. It does not react with nitrous acid, hence the nitrogen atom is tertiary in nature.

3. When A is treated with hydrochloric acid, a hydroxyl group is replaced by a chlorine atom. This

suggests that the functional nature of the oxygen atom is alcoholic.

4. Furthermore, the absorption spectrum of the chloro derivative is almost the same as that of the

parent compound. This suggests that the hydroxyl group is in a side chain.

5. The sulphur did not give the reactions of a mercapto compounds nor of a sulphide. The unreactivity

(i.e., stability) of this sulphur atom led to the suggestion that it was in a heterocyclic ring.

6. Oxidation of A with nitric acid gives the compound C5H5O2NS. It is a monocarboxylic acid and identical

with 4-methylthiazole-5-carboxylic acid (I).

7. From the above fact it is clear that A has a side chain of two carbon atoms in place of the carboxyl

group in (I)


8. The side chain may be either –CH2-CH2-OH or –CH(OH)-CH3. The second alternative –CH(OH)-CH3 is

excluded by the fact that A does not give the iodoform test, and that A is not optically active. Hence the

structure of A is (II) and is confirmed by the following synthesis.


Structure of compound B

1. The molecular formula of compound B is C6H9O3N3S

2. When heated with water under pressure at 200 0C, B gives sulphuric acid. It also forms sodium

sulphite when heated with concentrated sodium hydroxide solution. This suggests that B is a sulphonic

acid.

3. On treatment with nitrous acid, B evolves nitrogen, thus B contains one amino group.

4. Furthermore, since the evolution of nitrogen is slow, and the reaction of B with benzoyl chloride is

also slow, this suggests that B contains an amidine structure.

5. When B is heated with hydrochloric acid at 150 0C under pressure, we obtained compound C.

6. The formation of ammonia indicates the replacement of an amino group by a hydroxyl group. This

type of reaction is characteristic of 2- and 6-aminopyrimidines. This shows that B is a pyrimidine

derivative. Thus B is probably a 6-aminopyrimidine.


7. When B is reduced with sodium in liquid ammonia, a sulphonic acid group is eliminated with the

formation of an aminodimethylpyrimidine. This suggests that B is 6-amino-2,5-dimethylpyrimidine with

one hydrogen replaced by a sulphonic acid group.

8. The sulphonic acid group is joined to the methyl group at position 5. This is confirmed by treating 5-

ethoxymethyl-6-hydroxy-2-methylpyrimidine with sodium sulphite, whereby 6-hydroxy-2-

methylpyrimidyl-5-methanesulphonic acid is obtained. This is shown to be identical with compound C.

Thus B has the following structure,

This structure is confirmed by the following synthesis.


Thus the chloride hydrochloride of thiamine is,

This structure is confirmed by the following synthesis,


Riboflavin (Vitamin B2, Lactoflavin)

Occurrence

It occurs in yeast, green vegetables, milk, meat etc.,

Chemically vitamin B2 is closely related to the yellow, water soluble pigments known as flavins

and since it was first isolated from milk it has the name lactoflavin.


Riboflavin is a constituent of a group of enzymes called flavoproteins. As with thiamine, the

enzymes are necessary in the breakdown of the glucose to form energy.

It is essential for a healthy skin and for good vision in bright light.


If the individual ingest more riboflavin than their body needs, the urinary excretion will increase,

if the intake is inadequate, the body maintains its supply very carefully and the urinary excretion

will practically stop.

Requirements

Infants - 0.4 – 0.6 mg / day


Adult male - 1.5 – 1.8 mg / day

Adult female - 1.1 – 1.4 mg / day

Pregnant women - 1.4 – 1.7 mg / day

Lactating women - 1.6 – 1.9 mg / day

Deficiency

It is characterized by the development of fissures (gpsT) developing in the lips and the corners

of the mouth (Cheilosis).

Sore tongue.

Dermatitis (Njhy; myw;rp) in face.

Eyes become itchy and vision becomes poor in dim light.

The skin loses hair, it becomes dry and scaly.

Growth is arrested.

Structure


Pyridoxine (Vitamin B6)

Occurrence

The richest sources are yeast, rice polishing, grains and cereals, leafy vegetables, liver, eggs,

meat etc.,


The functions of pyridoxine are closely related to

protein metabolism

the synthesis and breakdown of amino acids

conversion of tryptophan to niacin

the production of antibodies

the formation of heme in hemoglobin

the formation of hormones important in brain function and others.

Requirements

Infants - 0.3 mg / day


Adults - 1.6 – 2.0 mg / day

Pregnant &


Lactating women - 2.5 mg / day

Deficiency

Deficiency of vitamin B6 is extremely rare. Nervous disturbances such as irritability, insomnia,

muscular weakness, fatigue and convulsion have been recorded in infants.

Structure

Structural elucidation of Pyridoxine

1. The molecular formula of pyridoxine is C8H11O3N.

2. When treated with diazomethane, pyridoxine forms a monomethyl ether which on acetylation give a

diacetyl derivative. It suggests that the three oxygen atoms in pyridoxine are present as hydroxyl groups.

3. Among the three hydroxyl groups, one is readily methylated, hence this one is probably phenolic –OH.

The other two hydroxyl groups groups are alcoholic.

4. The UV spectrum of pyridoxine shows that it is similar to that of 3-hydroxypyridine. Hence pyridoxine

is a pyridine derivative with the phenolic group in position 3.

5. Since lead tetra-acetate has no action on the monometyl ether of pyridoxine, this leads to the

conclusion that the two alcoholic groups are not adjacent.

6. When this methyl ether is very carefully oxidized with potassium permanganate, we get

methoxypyridinetricarboxylic acid, C9H7O7N. This acid give a blood red colour with ferrous sulphate,

which is a characteristic reaction of pyridine-2-carboxylic acid. Thus one of the three carboxyl groups is

in the 2-position.


7. When the methyl ether of pyridoxine is oxidized with alkaline permanganate, we get carbon dioxide

and the anhydride of a dicarboxylic acid, C8H5O4N. Thus these two carboxyl groups are in the ortho-

position.

8. Furthermore, this anhydride did not give a red colour with ferrous sulphate. This suggests that there is

no carboxyl group in the 2-position.

9. Thus the tricarboxylic acid could have either of the following structures.

10. Now pyridoxine methyl ether contains three oxygen atoms (one as methoxy and the other two

alcoholic), therefore it is possible that two carboxyl groups in the tricarboxylic acid could arise from two

–CH2OH groups and the third from a methyl group, i.e., pyridoxine could be either of the following.

11. When pyridoxine methyl ether was oxidized with barium permanganate, the product is a

dicarboxylic acid, C9H9O5N, which did not give a red colour with ferrous sulphate. Thus there is no

carboxyl group in the 2-position. Also the dicarboxylic acid formed an anhydride, thus the two carboxyl

groups must be in the ortho-position.

12. Thus the structure of this dicarboxylic acid is either I or II.


13. Various studies show that the anhydride formed from I and not from II. Hence, on the foregoing

evidence pyridoxine is,

This structure has been confirmed by the following synthesis.


Ascorbic acid (Vitamin C)

Occurrence

Raw fresh vegetables contain vitamin C.

Tomato, leafy vegetables, citrus fruits, cabbage are also contain vitamin C.


It regulates oxidation-reduction potential inside the cell by acting as a hydrogen carrier.

It regulates carbohydrate metabolism.


It plays a major role in wound healing by producing connective tissue.

It helps in the absorption of iron from the intestine.

It provides resistance power against toxins, cold and stress conditions.

Requirements

Infants - 35 mg / day

Children - 40 mg / day

Adults - 45mg / day

Pregnant & - 60 mg / day

Lactating women - 80 mg / day

Deficiency

Deficiency of this vitamin causes scurvy. It is characterized by internal bleeding. Bleeding is more

common in the gums. It is due to fragility (easily broken) of capillaries.

It causes malfunction of bones and teeth.

It causes increase brittleness of bones and teeth.

It also causes anaemia.

It causes delayed blood clotting.

Wound healing is delayed.

Structure


Structural elucidation of Ascorbic acid

1. The molecular formula of ascorbic acid is C6H8O6.

2. Since the compound forms a monosodium and monopotassium salt, it is thought that there is a

carboxyl group present.

3. Ascorbic acid behaves as an unsaturated compound and as a strong reducing agent. It also forms a

phenylhydrazone and gives a violet colour with ferric chloride. All this suggests that a keto-enol system

is present. i.e.,

4. On boiling with hydrochloric acid, it gives furfuraldehyde. This suggests that ascorbic acid contains at

least five carbon atoms in a straight chain and a number of hydroxyl groups.

5. On oxidation with aqueous iodine solution, it gives dehydroascorbic acid. Two atoms of iodine are

used and two molecules of hydrogen iodide are produced. This means that two hydrogen atoms are

removed from ascorbic acid.


6. Dehydroascorbic acid is neutral and behaves as the lactone of a monobasic hydroxy acid. On

reduction with hydrogen sulphide it is reconverted into ascorbic acid. Since the oxidation product,

dehydroascorbic acid is a lactone, then ascorbic acid itself is a lactone.

7. Ascorbic acid can form salts, due to the presence of enol group. All these reactions are due to the

presence of an α-hydroxyketone group in ascorbic acid.

8. The final result is the removal of two hydrogen atoms to form dehydroascorbic acid.

9. When dehydroascorbic acid is oxidized with sodium hypoiodite, oxalic acid and L-threonic acid are

produced. The structure of L-threonic acid has been shown to be IV. The formation of oxalic acid and L-

threonic acid suggests that dehydroascorbic acid is III. Thus ascorbic acid is I. All the foregoing reactions

may be given as follows. The dehydroascorbic acid is formed from ascorbic acid via II.

10. The ring in ascorbic acid has been assumed to be five and not six-membered. Numerous factors

support the presence of five-membered ring in ascorbic acid.


Finally the structure of ascorbic acid has been confirmed by the following synthesis.

Antibiotics

Antibiotic is defined as a drug derived from living matter of micro-organism which either

prevents the growth of other micro-organism or destroy them.

Antibiotics are obtained from micro-organisms such as fungi, bacteria etc.,

All the chemical substances obtained from living cells cannot be considered as antibiotics as the

antibiotics have to satisfy certain conditions, which are,

It should be effective even at low concentration.

It should kill one or more species of the micro-organism.

It should not have significant toxic side effect.


It must be effective against a pathogen.

It must be stored for a long time without appreciable loss of its activity.

Antibiotics should be completely eliminated from the body after its administration has been

stopped.

Classification

The Penicillins

Penicillin was discovered by Alexander Fleming in 1928. It is very important and widely used

antibiotic and hence it is called queen of drugs.

It was first extracted from the mould of penicillium notatum.

Penicillin is effective against gram positive and gram negative cocci and some gram positive

bacilli.

It is bacteriostatic in action but when given in certain concentration it can act as a bactericidal

agent.

The basic structure of the penicillins consists of a thiazolidine ring fused with a β-lactam ring.

These two rings constitute the fundamental nucleus of all the penicillins, namely 6-

aminopenicillinic acid.

The molecular formula of penicillin is C9H11N2O4SR. Depending on the nature of R, there are six

natural penicillins are found.


The basic structure of all penicillins is shown in the fig.

S.No. Name of the penicillin Structure of R

1. F -CH2-CH=CH-CH2-CH3

2. Dihydro F -CH2-CH2-CH2-CH2-CH3

3. G -CH2-C6H5

4. K -CH2(CH2)5-CH3

5. X -CH2-C6H4-OH(p)

6. V -CH2-O-C6H5

Structural elucidation of Penicillin G

1. The general molecular formula of penicillins is C9H11N2O4SR.

2. The penicillins are all strong monobasic acids as they form salts.

3. From various studies it is found that no free amino group and free thiol group are present.

4. They are hydrolysed by hot dilute inorganic acids, one carbon atom is eliminated as carbon dioxide

and two products are obtained in equimolecular amounts. One being an amine, i.e., penicillamine and

the other an aldehyde, i.e., penilloaldehyde.

5. All the penicillins give the same amine, but different aldehydes. Hence we may conclude the latter

i.e., penilloadehyde contains the R group.


Structure of Penicillamine

1. The molecular formula is C5H11NO2S.

2. This compound give colour reactions with sodium nitroprusside and ferric chloride which are

characteristic of the thiol group (-SH).

3. Electrometric titration shows three pKa values. These correspond to carboxyl, α-amino and thiol

groups i.e., the penicillamine is a cysteine derivative.

4. Since penicillamine combined with acetone to give an isopropylidine derivative which no longer

contained as free amino or free thiol group and is reconverted into penicillamine on hydrolysis.

This suggests that these two groups are attached to adjacent carbon atoms.

5. Oxidation of penicillamine with bromine water gave a sulphonic acid which is a characteristic of

thiol.

6. The Kuhn-Koth determination of methyl side chains gave a very low value. This suggests that the

penicillamine contains an isopropyl end group and not a methyl end group.

From the foregoing evidences the penicillamine is β,β-dimethyl cysteine.

Synthesis of Penicillamine


Structure of Penilloaldehyde

1. The molecular formula is C3H4NO2R.

2. On vigorous hydrolysis, all the penilloaldehydes give a substituted acetic acid and

aminoacetaldehyde. Thus, the penilloaldehydes are the acylated derivatives of

aminoacetaldehyde.

3. As pointed out, the acid hydrolysis of penicillin gives penicillamine, penilloaldehyde and carbon

dioxide. The formation of carbon dioxide gave rise to the belief that it is formed by the ready

decarboxylation of an unstable acid. Such an acid is a β-keto acid. So a possible explanation is

that penilloaldehyde carboxylic acid (penaldic acid) is formed as an intermediate in the

hydrolysis of penicillin.


The combination of penilloaldehyde and penicillamine to form penicillin

1. The hydrolysis of penicillin with dilute alkali or with enzyme penicillase produces penicilloic acid which

readily eliminates a molecule of carbom dioxide to form penilloic acid. This suggests that a carboxyl

group is in the β-position with respect to an electron attracting group.

2. Penilloic acid, on hydrolysis with aqueous mercuric chloride gives penicillamine and penilloaldehyde.

This hydrolysis is characteristic of compounds containing a thiazolidine ring. Thus, penilloic acid could be

(I).

Hence if, (I) is penilloic acid then penicilloic acid would be (II).

3. On the basis of the foregoing evidences, two structures are possible for penicillin. They are given as

follows,


4. The infra-red spectra and X-ray analysis of many penicillins showed the presence of a β-lactam ring.

Synthesis of Penicillin G (Vigneaud synthesis)

This synthesis consists of two steps.

1. In the first step, 2-benzyl-4-methoxymethylene-5-oxazolone (III) is prepared.

2. In the second step, (III) is combined with penicillamine (IV) to form penicillin G (benzyl

penicillin).


Chloramphenicol (Chloromycetin)

The trade name of chloramphenicol is chloromycetin.

It is a broad spectrum antibiotic originally produced from S.Venezuelx.

It is very effective in the treatment of typhoid fever.

Properties

Chloramphenicol is a stable, neutral compound, bitter in taste with a sharp melting point of 150

0C.

It is soluble in many organic solvents but is sparingly soluble in water.

It is optically active (laevorotatory).

Structural elucidation of Chloramphenicol

1. The molecular formula of chloramphenicol is C11H12Cl2N2O5.

2. Its ultraviolet spectrum is similar to that of nitrobenzene.

3. The presence of a nitro group was confirmed by the reduction of chloramphenicol with tin and

hydrochloric acid followed by diazotization and then coupling to give as orange red precipitate

with β-naphthol.


4. When reduced with palladium, it gives a product which has an absorption spectrum similar to

that of p-toluidine and the solution contains ionic chlorine.

5. Chloramphenicol is converted into a diacetyl derivative on treatment with acetic anhydride in

pyridine. The base obtained from chloramphenicol forms a triacetyl derivative on similar

treatment. Thus, chloramphenicol contains two hydroxyl groups.

6. Chemical analysis on chloramphenicol indicates the absence of free carbonyl and amino groups

in the molecule.

7. The hydrolysis of chloramphenicol with acid or alkali produces dichloroacetic acid and an

optically active base, C9H12N2O4.

Hence, in order to arrive at the structure of chloramphenicol we must establish the

structure of the base.

Structure of the base

1. The molecular formula of the base is C9H12N2O4.

2. Analysis of the base shows the presence of a primary amino group in the molecule.

3. As the base does not produce violet colour with ferric chloride, the base does not have phenolic

group and alcohol groups only are present in the base.

4. When the base is treated with methyldichloro acetate, it reformed chloramphenicol.

5. When the base is treated with periodic acid, two molecules of the periodic acid are consumed

with the formation of one molecule each of ammonia, formaldehyde and p-nitrobenzaldehyde.

6. The above reaction clearly indicates that the base contains,

a propyl group in the para position to a nitro group

an amino group is present on the second carbon atom of the propyl group.


7. The foregoing discussions will clearly indicate the structure of base as 2-amino-1-p-

nitrophenylpropane-1,3-diol as below,

8. It is to be noted that the base alone reacts with periodic acid and not the chloramphenicol. This

clearly indicates that two hydroxyl groups are not present on the adjacent carbon atoms in

chloramphenicol.

9. Further, the amino group in the molecule is experiencing steric hindrance. In order to explain

the above facts the structure of chloramphenicol must be as follows,

The above structure is confirmed by the following synthesis.

Unit - III W

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